Sulfur-containing derivatives of 2-methyl-4-hydroxymethyl-5-methylene-pyridine

ABSTRACT

AND R2 represents lower acyl, lower unsaturated alkyl, unsubstituted alkyl and substituted alkyl; with the provision that when R1 represents -S-, R2 is other than ethyl, Beta -chloroethyl or Beta -hydroxyethyl.   WHEREIN R1 represents   For descreasing the blood cholesterol level, ameliorating dysfunctions of the central nervous system and increasing the tolerance of animals to a deficiency of oxygen, compounds of the formula:

United States Patent [1 1 Schorre et al.

[451 Aug. 28, 1973 SULFUR-CONTAINING DERIVATIVES 0F Z-METHYL 4-HYDROXYMETHYL-5- METHYLENE-PYRIDINE [75] Inventors: Gustav Schorre, Darmstadt,

Germany; Herbert Nowak, Altdorf/Uri, Switzerland [73] Assignee: Merck Patent Gesellschaft mit beschrankter Haftung, Darmstadt, Germany [22] Filed: July 19, 1971 [21] Appl. No.1 164,123

Related U.S. Application Data [63] Continuation-impart of Ser. No. 735,182, June 7,

I968, Pat. No. 3,625,949.

[30] Foreign Application Priority Data June 8, 1967 Germany M 74311 Apr. 18, 1968 Germany P 17 70 222.6

[52] U.S. CL... 260/294.8 G, 260/243 B, 260/247.l, 260/268 S, 260/293.69, 260/294.8 D,

260/294.8 F, 260/294.8 C, 260/294.8 J,

[5 1] Int. Cl. C07d 31/50, C07d 31/48 [58] Field of Search 260/294.8 R, 294.8 G

[56] References Cited OTHER PUBLICATIONS Roberts et al., Basic Principles of Organic Chemistry, Benjamin Publishers, Page 806, (1965) OD 251 R 58 C6 Karrer, Organic Chemistry, 4th English Edition, Page 928, Elsevier Pub. Co. (NY) 1950.

Primary Examiner-Alan L. Rotman Attorney-l. William Millen et al.

[ 5 7 ABSTRACT For descreasing the blood cholesterol level, ameliorating dysfunctions of the central nervous system and increasing the tolerance of animals to a deficiency of oxygen, compounds of the formula:

CIIrOII and R represents lower acyl, lower unsaturated alkyl, unsubstituted alkyl and substituted alkyl; with the provision that when R represents S, R is other than ethyLB-chloroethyl or B-hydroxyethyl.

12 Claims, No Drawings CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of copending application Ser. No. 735,182, filed June 7, 1968, now U.S. Pat. No. 3,625,949, issued Dec. 7, 1971, and contains claimed subject matter which was cancelled in the aforesaid application in response to a restriction requirement; thus, this application obtains the benefits of the provisions of 35 USC 120 and 35 USC 121.

This invention relates to a group of novel sulfurcontaining pyridine derivatives and in particular to compounds suitable for improving animal tolerance to states of oxygen deficiency and the like.

Particular aspects of this invention, therefore, are to provide novel chemical compounds as well as processes and intermediates for their manufacture.

Additional aspects comprise pharmaceutical compositions based on the compounds of this invention, and also methods of administering same to animals.

Upon further study of the specification and appended claims, other aspects and advantages of this invention will become apparent.

Regarding the novel chemical compounds of this invention, they include compounds of Formula I and pharmaceutically acceptable acid addition salts thereof. Formula I is as follows:

imI Tour-a n; C-

wherein R represents 9 1 S or -S:

and

R represents lower acyl, lower unsaturated alkyl, or alkyl optionally substituted by halogen, OH, lower alkoxy, SH, lower alkylthio, optionally functionally modified carboxy and/or with the provision that, if R S, R represents a residue other than ethyl, B-chloroethyl or B-hydroxyethyl; and wherein R and R being identical or different, represent H or lower alkyl residues, which can also be combined to form a 5- or 6-membered alkylene chain optionally containing one or more hetero atoms of N, O or S.

The compounds of Formula I and slats thereof are pharmacologically efficacious.

In particular they lower the cholesterol blood level and therefore are to be considered as effective against atherosclerosis. The efficiancy is to be seen from corresponding animal experiments.

By administering these compounds in the below indicated daily dosages to young cocks, which obtain a feed with a high percentage of lipids, in the fourth week after beginning the following change for the cholesterol level in blood was found. Comparison experiments were carried out by administering ethyl-B-(4- chlorophenoxy)-isobutyrate, a substance well known as a hypolipidemic agent, e.g., from Am. Heart J., May 1968, page 707. The change of plasma cholesterol is indicated in the following in comparison to control animals which got the same feed, however no pharmacologically active compound.

Compound daily dosage Change of (mg/kg body plasma cholesterol weight) in the fourth week Compounds of above formula I, wherein R, S and R CH; I00 32 C H 32 C H I00 48 C I-LNH, 100 49 C l! 50 57 C,H, 5O 35 C I-I, 5O 26 C I-I 5O 30 C5 |oCH OH 50 20 ethyl-a-(4-chlorophenoxy)- isobutyrate (comparison substance) 300 +43 The comparison substance ethyl-a-(4-chlorophenoxy) isobutyrate was administered in a relatively high dosage of 300 mg/kg, because no more favourable influence on the blood cholesterol level was obtained in lower dosages.

From the above results it is to be seen that the compounds I show an outstanding hypolipidemic efficiency.

Additionally compounds of Formula I and salts there of are highly effective in ameliorating dysfunctions of the central nervous system, based on activating effects primarily on the lymbic system. These novel compound differ from known neurotropic agents by a special activity profile. The compounds show a distinct efficiency on the electric cerebral activity combined with a remarkably favourable influence on the lipid metabolism.

Besides, the compounds of Formula I and salts thereof improve the tolerance of animals to oxygen deficiency. For example, in experiments on rats, the test animals were subjected to a subatmospheric pressure corresponding to an altitude of about 12,000 meters, and then the electroencephalogram of the test animals was continuously recorded by way of three lead wires attached to the scalp. After the intraperitoneal administration of 100 mg of a compound of Formula I or salt thereof, for example, 2-methyl-3-hydroxy-4- hydroxymethyl-Smethylthiomethylpyridine, the electroencephalogram is compared. This procedure was repeated on seven successive days, and it was discovered that animals treated in this manner exhibited a marked improvement in their tolerance to diminished oxygen concentrations. It is particularly noteworthy that the increased tolerance shows up immediately after injection, whereas in a comparative experiment with identical dosages of the conventional compound bis-[2- methyl-3hydroxy-4-hydroxymethyl-pyridyl-( 5 methyl]-disulfide employed for the same purpose, no such immediate effect can be attained. Several compounds embraced by the above Formula I exhibit a physiologically protective effect against high intensity radiation.

For example, compounds of Formula I, which contain the radical C O II Rzz-CHz-CII and salts thereof show such a protective effect.

Additionally, the compounds of Formula I and salts thereof are useful to treat the types of pathological conditions often treated with the known bis-(3-hydroxy-4- hydroxymethyl-2-methyl-pyridyl-(5)-methyl)- disulfide.

The compounds according to the present invention may be administered for the following indications:

Atherosclerosis, organic psychic syndromes in re gressive processes; nervous exhaustion and insufficiency during the involution period, neurasthenic syndromes of constitutional origin. executive disease; posttraumatic craniocerebral disorders, apoplexy, encephalitis and intoxications (especially in chronic alcoholism Parkinsonism. Mental and psychic retardation of development during childhood, For interval therapy of migraine and long-term therapy of idiopathic trigeminal neuralgia.

As further compared to the above-mentioned known drug, bis- ]Z-methyl-3-hydroxy-4-hydroxymethylpyridyl-(S)-methyl]-disulfide, the compounds of this invention are distinguished by the fact that the solubility thereof in water and/or lipoids can be varied by tailoring the residue R both with respect to the length of chain and the choice of more or less polar substituents. For example, compared to the known disulfide, the compound 2-methyl-3-hydroxy-4-hydroxymethyl-5- methylthiomethyl-pyridine of this invention is ten times more soluble in water, and the compound 2-methyl-3- hydroxy-4-hydroxymethyi-S-methylsulfinylmethylpyridine is 100 times more soluble in water.

Compounds of the above-mentioned Formula I substituted in the residue R by amino and/or carboxy groups exhibit the additional advantage that they are water-soluble in the physiological pH-range, i.e., pH 5 to 8, thus being particularly suitable for the preparation of injection solutions. in contradistinction thereto, the above-mentioned known disulfide is insoluble in water within the physiological pH-range.

Compounds of the aforementioned Formula 1 containing longer alkyl residues in the R residue are distinguished, as compared to the conventional disulfide, by increased lipoid solubility. These compounds can penetrate cell membranes relatively rapidly and are more satisfactorily absorbed by the lipoid-rich nerve tissue.

To prepare the above-mentioned compounds of Formula l and the salts thereof, several alternative processes can be employed as follows:

a. liberating a free hydroxy group and optionally free amino groups from a starting compound of Formula ll or the salts thereof HaC wherein CHQSX wherein R and R being identical or different, represent OH groups which are optionally functionally modified; and X represents H or an alkali or alkaline earth metal cation, preferably Na", or an optionally substituted alkyl, aryl or aralkyl residue, or an undesired acyl residue, or the residue (llHzRg wherein c. a pyridine derivative of the Formula lV or a salt thereof wherein Z represents a sulfonic acid residue, particularly ptoluenesulfonyloxy; halogen, preferably Cl or Br; or the residue and R and R have the meanings set forth for Formula Ill, is reacted with a mercapto compound of Formula V YS-R wherein Y represents H or an alkali or alkaline earth metal cation, preferably Na; and

R has the above indicated meanings;

d. a pyridine derivative of Formula Vl, as set out below, or a salt thereof is treated with a reducing agent or, if desired, with a nucleophilic reagent, particularly a base:

R represents CH R or a free or functionally modified formyl group; and

with the provision that R is always when R is Cl- R and R is S; and that R is always a free or functionally modified formyl group when R represents and R represents S; and that R is always and R is CH R and wherein R R and R have the meanings indicated in Formula l or III, respectively, and wherein, additionally,

undesired substituents may also be present in the residue R which undesired substituents can be split off by reduction, or can be converted into the desired substituents for R as set forth in the above definition;

e. a pyridoxamine derivative of Formula Vll or a salt thereof, V

Cll2-Rr-R:

' tuted by halogen, OH, lower alkoxy, SH, lower alkylthio, carboxy, functionally modified carboxy and/or g. in a compound of the above Formula I or in the salts thereof, containing, however, in the residue R 15 C-C unsaturated bonds, the undesired substituents are split off, or the unsaturated CC multiple bonds are hydrogenated; or the desired substituents and/or CC unsaturated bonds are introduced.

In addition, it is also possible to split off any remaining protective groups in the residues R and R after conducting the processes (b) to (g), under the conditions of process (a).

Furthermore, if desirable, the thus-obtained compounds of the above-mentioned Formula I wherein R S-, can be oxidized to the corresponding compounds having the substituent Ba i-Q Still further, the free bases of Formula I can be converted into the acid addition, quaternary ammonium or the tertiary sulfonium salts thereof. Conversely, the

free bases can be liberated from the acid addition, quaternary ammonium or tertiary sulfonium salts thereof. In the compounds of Formula l of this invention, the residue R represents the compounds having the residue R =S- being preferred.

The residue R, in the compounds of Formula l can represent the following:

alkyl, preferably alkenyls, such as vinyl, allyl, propenyl,

or butenyl; or alkynyl residues, such as ethynyl or propargyl. Preferred residues are vinyl and propargyl.

Of special importance, however, are compounds of the above Formula I wherein R represents an alkyl residue, optionally substituted as indicated in Formula I. The alkyl residue can be straight-chain or branched, and generally has no more than 20 carbon atoms. Suitable alkyl residues are long chain alkyls, such as hexyl, heptyl, octyl, nonyl, decyl, dodecyl, eikosyl and lower alkyls such as methyl, n-propyl, isopropyl, n-butyl, isobutyl and pentyl. Particularly preferred are compounds wherein R, represents n-pentyl, n-butyl or methyl.

An alkyl residue R, can be monosubstituted, or poly- S substituted at any and all carbon positions, but prefera- For halogen substitution, Cl and Br are preferred, Additional substituents for the alkyl residue R are OH; lower alkoxy, such as methoxy and/or ethoxy, mercapto groups; and/or lower alkylthio groups, particularly methylthio. In particular preferred residues R are CH Ol-l and C l-l CH OH.

Alkyl can also be substituted by amino groups -NR R.,, wherein R and/or R represent H or lower alkyl, and wherein alkyl residues R and R, can also be joined together to form an alkylene residue, optionally by way of a nitrogen, oxygen or sulfur atom. Thus, together with the N atom of the amino group, the alkyl residues can form, for example, a piperidino, morpholino, piperazino or thiomorpholino residue. Preferably, the substituents R and R are identical and represent H or CH; or C l-l Examples of amino-substituted alkyl residues R include, but are not limited to: 2- aminoethyl, 3-aminopropyl, 3-amino-2-methylpropyl, 4-aminobutyl, as well as the corresponding N-methyl, N-ethyl, N-propyl, N-butyl, N,N-dimethyl, N,N-diethyl, N-methyl-N-ethyl, and piperidino derivatives. In this connection, particularly preferred is Z-aminoethyl and dimethylaminoethyl. I

The alkyl residue R can be further substituted by a free carboxy group or a functionally modified carboxy group, in particular by an esterified or amidated carboxy group of a total of up to 8 carbon atoms. A suitable esterified carboxy residue is, for example: lower carbalkoxy, such as carbomethoxy, carbethoxy, or also carbobenzoxy. A particularly suitable amidated carboxy residue is -CONl-l,. However, the hydrogen atoms of the amino group can also be substituted by lower alkyl residues which can be joined with one another, if desired by an additional hetero atom in the same manner as N R R In addition to the residue COHN also suitable are the N-rnethyl, N-ethyl, N-propyl, N- butyl, N,N-dimethyl, N,N-diethyl, N,N-dipropyl, N- methyl-N-ethyl amides, as well as the piperidides, piperazides and morpholides or thiomorpholides. Preferred substituents are COOH, COOC,H,,, CONH CON(CH and CON(C l-l Optionally, it is also possible for the alkyl residue R, to contain different substituents, for example, NH and COOH groups, at the same time. Thus, R, can represent for example, an w-amino-w-carboxyalkyl residue,

CHr-CH-C O OH wherein the carboxy group can optionally also be esterified or amidated, or otherwise functionally modified.

Preferred compounds of the above Formula I are those wherein R represents the following: COCH allyl, propargyl, alkyl containing no more than 20 C atoms as 3 a 'n o r s 1n T ISa Io zh C l-l especially C 11 CI'lg and CH lower alkyl substituted by NR R OH, COOCH;, especially C,H NH,, --C=H,N(CH,),, CH,OH, C =,H C- l-l Ol-l,

car-( 111 0H Among the preferred products of Formula I wherein R -S, the following examples are set forth:

Z-methyl-3-hydroxy-4-hydroxymethyl-5 -(methylthiomethyl)-pyridine,

Z-methyl-3-hydroxy-4-hydroxymethyl-5 allylthiomethyl)-pyridine,

Z-methyl-3-hydroxy-4-hydroxy-methyl-5- (propargylthiomethyl)-pyridine,

Z-methyl-3-hydroxy-4-hydroxymethyl-5- (isopropylthiomethyl)-pyridine 2-methyl-3hydroxy-4-hydroxymethyl-5 n-butylthiomethyl )-pyridine,

Z-methyl-3-hydroxy-4-hydroxymethyl-5- (hydroxymethylthiomethyl)-pyridine,

2-methyl-3-hydroxy-4-hydroxymethyl-5-(B- mercaptoethylthiomethyl)-pyridine,

2-methyl-3-hydroxy-4-hydroxymethyl-S- (methylthioethylthiomethyl )-pyridine,

Z-methyl-3-hydroxy-4-hydroxymethyl-5- carbethoxymethylthiomethyl)-pyridine,

2-methyl-3-hydroxy-4-hydroxymethyl-5-(B- aminoethylthiomethyl )-pyridine,

2-methyl-3 -hydroxy-4-hyd roxymethyl-S ,B-

dimethylaminoethylthiornethyl)-pyridine,

2-methyl-3 -hydroxy-4-hydrox ymethyl-S B-amino-flcarboxyethylthiomethyl)-pyridine.

2-methyl-3-hydroxy-4-hydroxymethyl-5-acetyl-thi omethyLpyridine,

2-methyl-3-hydroxy-4-hydroxymethyl-5 -pivalyl-thiomethyl-pyridine,

2-methyl-3-hydroxy-4-hydroxymethyl-5- carbomethoxyethyl-thiomethyl-pyridine,

Z-methyl-3-hydroxy-4-hydroxymethyl-5 -B- acetoxyethyl-thiomethyl-pyridine,

S-hydroxy-4-hydroxymethyl-3-[(2-cyanoethyl)- thiomethyll-fi-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3-[(2-ethoxy )ethylthiomethyl1-6-methyl-pyridine,

5 -hydroxy-4-hydroxymethyl-3-[ (2-hydroxy-npropyl )-thiomethyl ]-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3-[ 6-hydroxy-n-hexyl) -thiomethyl]-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3-[ 1,2-

diethoxycarbonyl )ethyl-thiomethyl]-6-methylpyridine,

5-hydroxy-4-hydroxymethyl-3-[( l-methyl-2- ethoxycarbonyl)ethyl-thiomethyll-fi-methylpyridine,

S-hydroxy-4-hydroxymethyl-3-[ (2,3-dihydroxy propyl-thiomethyl1-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- n thiomethyl-6-methyl-pyridine,

5-hydroxy-4-hydroxyrnethyl-3- n pentyl-thiomethyl- G-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- n hexyl-thiomethyl- G-methyl-pyridine,

5hydroxy-4-hydroxymethyl-3- n heptyl-thiomethyl- G-methyl-pyridine,

S-hydroxy-4-hydroxymethyl-3- n octyl-thiomethyl- G-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- n nonyl-thiomethyl- 6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- n decyl-thiomethyl- 6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- thiomethyl--methyl-pyridine,

dodecyln hexadecyl- -hydroxy-4-hydroxymethyl-3- n octadecylthiomethyl-6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- n eikosylthiomethyl-o-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- n propylthiomethyl-6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- thiomethyl)-6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- thiomethyl)-6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- thiomethyl)-6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- carboxyethyl)thiomethyll-6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3 [(5-oxo-hex3- en)thiomethyl] -6-methyl-pyridine, 5.-hydroxy-4-hydroxymethyl-3- [-(2-brom0propyl)- thiomethyl] -6-methyl-pyridine, 5-hydroxy-4-hydroxyrnethyl-3- [(2,3-dibromopropyl)thiomethyl] -6-methyl-pyridine,

5 -hydroxy-4-hydroxymethyl-3- [(3-hydroxy-3- bromopropyl)thiomethyl] -6-methyl-pyridine, yridine,

5-hydroxy-4-hydroxymethyl-3- [(3-chloro)-but-( l yl)thiomethyl] -6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- l-hydroxypropyl thiomethyl] -6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- thiomethyl] -6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- 2-ethoxyethyl)thiomethyl] -6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- [(2-dibutylamino)ethylthiomethyl] -6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3- [(3-aminopropyl)thiomethyl] -6-methyl-pyridine, 5-hydroxy-4-hydroxymethyl-3-carboxymethylthiomethyl-6-methyl-pyridine,

B- [(5-hydroxy-4-hydroxymethyl-6- methylpyridyl( 3 )-methyl)thio]-propionic acid,

5-hydroxy-4-hydroxymethyl-3- methoxycarbonyl)-ethyl]thiomethyl-6-methylpyridine,

S- [5-hydroxy-4-hydroxymethyl-6-methyl-pyridyl- (3)-methyllcysteine-ethylester 5-hydroxy-4-hydroxymethyl-3- [(Z-carboxylethyl thiomethyl] -6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- [(2,2-diethoxy-ethyl- 1 )]thiomethyl-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- methylaminomethylthiomethyl-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- dimethylaminomethylthiomethyI-G-methylpyridine,

S-hydroxy-4-hydroxymethyl-3- methylaminoethylthiomethyl-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- ethylaminoethylthiomethyl-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- dimethylaminoethylthiomethyl-6-methyl-pyridine,

5-hydroxy-4-hydroxymethyl-3- dipropylaminoethylthiomethyl-6-methyl-pyridine 5-hydroxy-4-hydroxymethyl-3- dihexylaminoethylthiomethyl-6-methyl-pyridine.

(3 -bromopropyl- (3-hydroxypropyl- (3-mercaptopropyl- [(3 -hydroxybutyl Additionally, the following compounds are preferred wherein the residue R represents,

2-methyl-3-hydroxy-4-hydroxymethyl-5- (methylsulfinylmethyl)-pyridine, 2-methyl-3-hydroxy-4-hydroxymethyl-5- (ethylsulfinylmethyl)-pyridine, 2-methyl-3-hydroxy-4-hydroxymethyl-S- (allylsulfinylmethyl)-pyridine, 2-methyl-3-hydroxy4hydroxymethyl-5- (propargylsulfinylmethyl )-pyridine.

In addition to the free bases of the above Formula I, the present invention likewise encompasses the salts thereof, i.e., acid addition salts, particularly with strong mineral acids, such'as sulfuric acid or a hydrohalic acid, e.g., hydrochloric acid or hydrobromic acid, and also the quaternary ammonium or tertirary sulfonium salts.

Of particular importance is 2-methyl-3-hydroxy-4- hydroxymethyl-5-methylthiomethyl-pyridine, pharmacologically highly efficacious, and the acid addition salts thereof, e.g., the hydrohalogenides thereof, particularly the hydrochloride or also the sulfate. Among the quaternary ammonium or tertiary sulfonium salts of this compound, the methoiodide is especially preferred.

Processes for the preparation of the compounds of this invention will now be described in greater detail:

a. In accordance with one process of the present invention, the compounds of Formula I are obtained by liberating hydroxy groups from a starting compound of the above set forth Formula II, containing functionally modified hydroxy groups in the 3- and/or 4-position.

As preferred starting compounds of this embodiment, substances of the above-mentioned Formula [I are selected wherein R and/or R represent acyloxy, particularly lower acyloxy, such as acetoxy, propoxy, butoxy, wherein acetoxy is preferred, or R and R together represent (in this connection R and R represent H or lower alkyl, or are together alkylidene or cycloalkylidene or aralkylidene of preferably up to 7 carbon atoms, such as methylene, ethylidene, isopropylidene, cyclohexylidene, benzylidene. In particular preferred are these compounds, wherein R and R represent, together with the C-atom connecting R and R alkylidene or cycloalkylidene or aralkylidene). Furthermore, the residues R and R; can, if desired, also be alkoxy, particularly lower alkoxy, such as CH O-, C H O or C ,H,O-.

In order to liberate the hydroxy group(s), saponifying alkaline reactants or hydrolyzing acid reactants are preferably employed, the latter being more preferred. Thus, acidic reactants are employed, for example, if an alkylidene residue is to be split off from the substituents R and R in case ofacidic hydrolysis, it is possible to can be liberated even with very dilute acid, e.g., 0.0lN H 80 lf starting substances of Formula II are selected wherein R and/or R represent acylated hydroxy groups (for example,

or benzoyloxy) the blocking groups can also be split off by means of alkalis, for example, by means of alkali hydroxide or carbonate, such as sodium or potasslum carbonate.

If desired, functionally modified hydroxy and/or amino and/or carboxy groups can likewise be liberated in the side chain R in this embodiment.

Preferred starting compounds for this embodiment are, for example, compounds of the above Formula 11 wherein:

' all steps being in accordance with methods known from the literature.

b. For the introduction of the residue R into a starting compound of Formula II! in accordance with the aforementioned mode of operation (b), suitable agents are those conventionally employed for the S-alkylation and S-acylation, respectively, as they are described, for example, in Houben-Weyl, Methoden der Organisehen Chemie" (Methods of Organic Chemistry), 4th Edition, Vol. 9 (i955), Georg Thieme Publishers, Stuttgart, pp. 19-7 et seq.

Primarily employed for the alkylation are the corresponding reactive esters containing a residue R particularly alkyl halogenides or alkyl sulfuric acid esters or alkyl sulfonic acid esters, particularly p-toluenesulfonates. For example, there are employed the corresponding, optionally substituted alkyl chlorides, bromides and iodides, or sulfates of the Formula R -halogen or (R SO wherein R, has the above-indicated meanings, such as, for instance, methyl iodide, propyl chloride, butyl bromide, B-chloroethylamine; a-amino-B- chloropropionic acid; B-chloroethylmercaptan, dimethyl sulfate, chloroformic acid esters, chloracetic acid esters, allyl bromide, propargyl chloride, methyl p-toluenesulfonate, propyl bromide or iodide, isopropyl bromide or iodide, sec.-butyl bromide, see-butyl iodide, diethyl sulfate, ethyl p-toluenesulfonate, (B-hydroxy)-ethyl p-toluenesulfonate, (B-chloro)-ethyl p-toluenesulfonate, chloracetic acid, bromacetic acid ester, ,B-piperidinoethyl chloride and bromide, n-(B- chloro[or-bromo] ethyl)-morpholine, N-(B-chloro [or -bromo] ethyl)-thiomorpholine.

Ethylenirnine can also be employed as the alkylating agent for introducing the aminoethyl residue.

01?; R5 and R6 together represent CH3CO or R5 and R4! together represent (CH )zC|O or R5 and Rstogether represent (CH3)2CO or R5 and R5 together represent CH0- or 0 l R5 and Bi each represents --0-JJGH or O 2=-(CH2): -NHC 0 0211,. R5 and Re each represents -O-( l 02115 or C O OH 2=CH2-CH R and R together represent These starting compounds can be produced, for example, by alkylation or acylation of a compound according to Formula ll, having in place of R H or Na respectively, with a halogen-R or an acyl halogenide,

respectively, optionally followed by oxidation of the 65 and, if desired, subsequently reacting the product with mie, 4. edition, Verlag Georg Thieme, Stuttgart, Vol. 9, page 97 ff. (1955).

The starting compounds III are suitably alkylated by combining the reactants in an inert solvent, if desired, under cooling. For example, a mercaptide of Formula Ill is introduced into an aqueous or alcoholic solution, and the alkylating agent, for example an alkyl halogenide or the dialkyl sulfate, is added in an equivalent amount or in a slight excess. The reaction can be conducted at room temperature, by allowing the reaction mixture to stand overnight, for example. If desired, it is also possible to operate at an elevated temperature; for instance, the alkylation can be conducted by heating the mixture for several hours on a steam bath.

In case starting compounds III are present wherein the residues R and R, represent free OH groups, it is advisable not to employ an excess of the alkylating agent in order to avoid an undesired O-alkylation in this manner. Optionally, the mixture is neutralized after the reaction is terminated. The desired final product generally precipitates from the solution during cooling.

It is furthermore possible, for example, to conventionally alkylate a mercaptan III in water or in an alcohol in the presence of an alkali or alkaline earth comacetate or a chlorinated hydrocarbon, such as chloroform, methylene chloride, trichloroethylene or ether, and evaporation of the extraction agent.

By reaction with an alkylating agent under the aforementioned conditions, it is also possible to exchange, in a starting compound of Formula Ill, an undesired residue X against a desired alkyl residue. By reacting a starting compound III containing an undesired abovedefined residue X with, for example, a methyl halogenide, particularly methyl iodide, a compound of the above Formula I is obtained, for instance, wherein R CH If desired, salts, e.g., sulfonium salts, of the starting compounds III can be employed for this alkylating splitting process.

In case starting compounds Ill are employed wherein X represents an optionally substituted undesired alkyl residue or also an aryl or aralkyl residue, which can likewise be substituted, the desired residue R is introduced by reaction with an alkylating agent under the conditions mentioned above, by transalkylation. Suitable starting compounds for this special modification of process (b) are, for example, compounds of the abovementioned Formula Ill which contain the substituent X -cocH,c,H, or -Cl-I Cl-l=CI-l and which can be transalkylated, for example, with CI-l l in a compound I (R S; R, CH,). It is also possible, in starting compounds Ill containing the residue X CH to replace this residue, e.g., by transalkylation with, for example, ClCl-l,COOI-I, by R CH COOI-I. The following compounds are exemplary for the starting products: 2-methyl-3hydroxy-4-hydroxymethyl-5phenacyl-thiomethyl-pyridine; 2-methyl-3-hydroxy-4- hydroxymethyl-Sbenzyl-thiomethyl-pyridine; and 2- methyl-3hydroxy4-hydroxymethyl-5methylthiomethyl-pyridine.

The more specific conditions for the execution of the transalkylation or acylation are described in Houben- Weyl, loc. cit., Vol. 9 1955), p. 190, or in Chem. Ber- [Chemical Reports] 83, (1950), 86, 1049(1953), and Ann. Chemie [Annals of Chemistry] 566, 139 (I950).

The starting compounds can be produced, for example, by alkylating a compound of the above Formula Ill under the conditions described above in (b).

ln the compounds of Formula II], the undesired residue X is removed by treatment with, e.g., an alkyl halogenide, particularly a methyl halogenide, such as methyl bromide or methyl iodide, with the simultaneous introduction of the desired residue R Insofar as starting compounds of the above Formula II] are employed wherein X represents the residue CH R,

N CH:

(R R, and R having the above indicated meanings), there is obtained in this embodiment of the process of this invention the desired final product of the abovementioned Formula I by reaction with an alkylating agent by alkylative splitting. In this alkylative splitting step, in the final analysis, the undesired residue X is likewise substituted by the desired residue R For this modification, suitable starting products are, e.g.: bis- [2-methyl-3 hydroxy-4-hydroxymethyl-pyridyl-( 5 methyl]-di- (or -mono-) sulfide, or the corresponding tertiary S-alkyl compounds, for instance, the S-methyl compounds (above Formula Ill wherein R and These starting compounds are obtainable, for example, by reacting a compound of Formula lll (X Na*) with a compound of Formula [V (Z l-lal) or a compound of Formula IV (Z Hal) with an alkali disulfide, e.g., Na s Compounds of Formula I wherein the residue R cn on can also be produced from the starting com pounds lll wherein X H, by reaction with formaldehyde. Suitably, a mercaptan or mercaptide III in an aqueous solution, to which is optionally added an inert organic solvent, particularly alcohol, is mixed for this purpose with an aqueous, preferably 40 percent solution of formaldehyde and allowed to stand several hous, e.g., overnight. In this connection, it is advantageous to employ an excess of formaldehyde.

In order to introduce a residue R CH; into a starting compound II wherein X H and R and R have the above-indicated meanings, a suitable alkylating agent is furthermore diazomethane, in particular. In this reaction, conditions are employed, for example, which are described in Neuere Methoden der praparativen organischen Chemie [More Recent Methods of Preparative Organic Chemistry], published by W. Foerst, Chemie Publishers, Weinheim (1949), 3rd Edition, Vol. I, pp. 359-4l2.

A substituent R, acyl can be introduced into a starting compound of Formula III (X H, alkali or alkaline earth metal cation or undesired acyl residue) by treatment with the conventional acylating agents.

For the acylation of the starting products III, carbonylic acids can be employed, or the reactive derivatives thereof customarily used for esterification purposes, for example, acid halogenides, particularly acid chlorides, acid anhydrides or also ketenes, in particular symmetrical acid anhydrides. The conditions for this particular embodiment are described, for instance, in

I-Iouben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], 4th Edition, Thieme Publishers, Stuttgart, Vol. 9 (1955), pp. 753 756. By reacting a starting product of Formula Ill (X H or Na) with, for example, an acetyl halogenide, particularly acetyl chloride or bromide, or acetic anhydride, or with a ketene, the acetyl residue can be introduced at the S atom. Besides, an acyl residue R can be introduced into a starting compound III (X H), by making.

a carboxylic acid react with the available starting product in the presence of a carbodiimide, in particular dicyclohexyl carbodiimide. Preferred are inert solvents which do not contain any active hydrogen, such as, for example, halogenated hydrocarbons, such as CI-ICl or CH Cl or nitrohydrocarbons, such as nitromethane, or acetonitrile or ethyl acetate.

Furthermore, compounds of the above Formula I wherein R represents acyl can be converted, by reacting the starting products III (X H) with a nitrile and hydrochloric acid to the corresponding iminothioetherhydrochloride or with isocyanate to the corresponding thiourethane-S-ester.

The thus-obtained intermediate products are thereafter hydrolyzed to the desired compounds of Formula I wherein R represents acyl. The procedure followed is, for example, that described in Houben-Weyl, ed. cit., 4th Edition, Vol. 9, pp. 763 et seq., or 831 et seq., or 819 et seq (1955). The iminothioether-hydrochlorides are hydrolyzed, for example, with hydrochloric acid/- water.

The acylation is suitably conducted under gentle conditions, insofar as R, and R represent free hydroxy groups in the starting compound III. If R and R are functionally modified hydroxy groups in the starting compound, it is possible also to operate under more vigorous conditions. In this manner of conducting the process, the OH groups of the starting compounds are preferably blocked.

Starting products of Formula III wherein an undesired acyl residue is contained as the substituent X are converted into the desired final products of the above Formula I by means of the above-mentioned acylating agents by transacylation.

In the alkylation or acylation process, it is possible to employ, in addition to the basic compounds of the above-disclosed Formula III, also the salts thereof, particularly the quaternary ammonium salts and/or optionally sulfonium salts and, in particular, the acid addition salts thereof as the starting compounds.

-c. In accordance with the present invention, the starting compound employed can also'be a pyridine compound of the above Formula IV. The residue R, is introduced into this compound by reaction with a mercapto compound of the above-mentioned Formula V, under approximately the same conditions as described above for the alkylation or acylation, respectively, of the starting product III.

In the starting compounds IV, Z halogen, preferably bromine or chlorine or a sulfonic acid residue, particularly 0SO C H,CI-I OSO --C,,H,Br; -OSO,C H,;

O--SO,-CH the p-toluenesulfonic acid residue being preferred, or the radical of a sulfuric acid ester of the formula (EJHrRs -0s Og-O-CH. I-Rt L 4:11.

are produced by reacting the above-mentioned starting products IV, particularly the corresponding 5- halogenomethyl derivatives, with a thiocarboxylic acid, or a thiocarbamic acid derivative or the corresponding alkali derivatives (above Formula V wherein R represents lower acyl). This reaction can be conducted, for example, in accordance with the conditions set forth in Houben-Weyl, ed. cit., 4th Edition, Vol. 9 (1955), pp. 749 et seq. Suitably, the reaction is accomplished in an appropriate solvent, e.g., an alcohol, especially a lower aliphatic alcohol, such as methanol, ethanol, propanol, isopropanol and n-butanol, or with dimethyl formamide. A preferred solvent is ethanol. It is advantageous to conduct the reaction in the presence of an alkali, for instance in an alcoholic potassium hydroxide solution. Generally, the process is conducted at room temperature; however, in certain cases, it is preferred to heat the reaction mixture or to boil same under reflux.

In a particularly advantageous embodiment, alcoholic potassium hydroxide solution is provided, for example, in a small excess, and the thiocarboxylic acid is then added; in this reaction, the potassium salt of the acid is formed. Then either a stoichiometric amount or an excess of the starting compound IV is added to the 1 alkaline solution of the thiocarboxylic acid salt. The thus-obtained compound of Formula I is then isolated in a conventional manner, e.g., by extraction with a suitable solvent; such as ether and, optionally, subsequent recrystallization.

In the event the residues R and R represent free hydroxyl groups in the starting product IV, the thioacylation is suitably conducted under gentle conditions. If R and R are present in the starting product as functionally modified hydroxy groups, it is possible to operate under more vigorous conditions, for example, at an elevated temperature.

(1. Compounds of Formula I can also be producted by the reduction of starting compounds of the abovementioned Formula VI or the salts of these compounds.

For example, a starting product of the abovementioned Formula VI containing the substituent can be converted into the corresponding compounds of Formula I containing the pyridine nitrogen in the unoxidized form, or containing the desired residue R S, by treatment with reducing agents, such as zinc/dilute hydrochloric acid or iron/hot acetic acid or phosphorus trichloride or bromide. Preferably, the reduction is carried out by heating with ammonium sulfide or heating with phosphorus trichloride, e.g., in chloroform, or by treating with iron powder in hot acetic acid. Likewise, suitable for converting a starting product of Formula Vl containing the substituent R NO or R S or S0 into a final product I containing the pyridine nitrogen in the unoxidized form, or which contains the desired residue R, S, is a catalytic reduction with conventional catalysts, e.g., percent palladium charcoal or Raney nickel in suitable solvents, such as ethanol or acetic anhydride. This reduction is conducted under conditions known from the literature, as described, for example, in Archiv Pharm. 287, 326 (1954); J. Org.

Chem.18, 534 (1953); Rec. Trav. Chim. Pays-Bas 70.

581 (1951); J. Pharm. Soc., Japan 71, 1092 (1952); I-Iouben-Weyl, Methoden der Organischen Chemie 4th Edition, Vol. 11/2, pp. 200 et seq., G. Thieme Publishers, Stuttgart.

In addition to the basic compounds of the above Formula VI, salts of these compounds can also be employed as starting comounds in the species (d) of the process of this invention.

Thus, it is possible, for example, to convert salts in accordance with Formula VI wherein is in place of R and him] [we] is in place of R (in this connection, alkyl represents an optionally substituted alkyl residue and W repre sents an equivalent of an anion, such as Cl, Br, I, 1/2 likewise by reduction, into the desired compounds I wherein R, S. For this purpose, processes are employed suitable for the reduction of amine-alkoxides to amines or for the reduction of O- alkylated sulfoxides to thioethers, for example, base metals, such as zinc with acids or complex metallic hydrides, such as sodium borohydride in ethyl alcohol or tetrahydrofuran. Furthermore, such salts of compounds VI (R Cl-l R can also be converted, by treatment with nucleophilic reagents, preferably with bases, such as aqueous alkali hydroxide or silver oxide, into the desired compounds of the above Formula I wherein R S. The conditions under which this special process can be conducted are described, for example, in J. Pharm. Soc. Japan 64, 210 (1944), or J. Org. Chem. 18, 534 (1953), as well as in J. Org. Chem. 32, I926 (1967) and J. Org. Chem. 32, 3233 (1967).

Furthermore, in the mode of operation (d), starting products VI containing as the substituent R on the pyridine ring a free or functionally modified formyl group are converted by reduction, in accordance with the processes conventional for the conversion of formyl groups into hydroxymethyl groups, into the desired final products of Formula 1. Preferred starting compounds for this particular species are compounds of Formula VI wherein R presents Cl-IO. For example, the following compounds VI can be employed as the starting products: 2- methyl-3hydroxy-4-formyl-5- methylthiomethyl-pyridine; 2-methyl-3-hydroxy-4- formyl-Scarbethoxymethylthiomethyl-pyridine; 2- methyl-3hydroxy-4-formyl-5aminoethylthiomethylpyridine; and 2-methyl-3hydroxy-4-formyl-5- dimethylaminoethylthiomethyl-pyridine. Suitable reduction agents are, e.g., complex metallic hydrides, in particular lithium aluminum hydride or sodium borohydride, base metals and acids, particularly zinc or iron/acetic acid, aluminum amalgam/water, aluminum isopropylate/isopropanol, as well as catalytically activated hydrogen. The more detailed conditions under which the reaction can be conducted are described more explicitly, for example, in Weygand-Hilgetag, pp. 154 169, Organisch-chemische Experimentierkunst, 3. edition, J. A. Barth-Verlag, Leipzig, 1964.

Preferred functionally modified formyl groups R in the starting products VI are acetals of lower alcohols, if desired, also of araliphatic alcohols, such as benzyl alcohol. The conditions for preparing these pyridoxal acetals (compounds VI wherein R represents, for example, CI-I(OC H are described in detail, for instance in I-Iouben-Weyl, ed. cit., Vol. 6/3 (1965 pp. 199-270. On the pyridoxal acetals, the hydroxy] group in the 5-position can be substituted by halogen in a manner known from the literature, and the halogen subsitutent can be replaced by SH OR R,R

The splitting of these acetals with the simultaneous reduction of the 4-carbonyl group to the 4'-hydroxy group is preferably conducted with the aid of catalytically activated hydrogen under conditions described in greater detail in I-Iouben-Weyl, ed. cit., Vol. 6/3 (1965), pp. 277 278.

Insofar as substituents are present in the starting compound VI which are reducible in the residue R for example, the residues described below under (g these residues are optionally also reduced during process (d).

e. A pyridine derivative of the above-mentioned Formula Vll can be converted into a final product of Formula 1 containing a hydroxy group in the 4'-position, by treatment with nitrous acid. The conditions for this re-' action are described, for example, in Houben-Weyl, ed. cit., Vol. 11/2 (1958), pp. 133 157. For this mode of operation, compounds of Formula Vll or the salts thereof are employed which contain as the substituent R preferably a free amino group, or an amino group provided with a triphenyl-methyl group or with acyl residues, such as onitrophenyl sulfenyl, l-adamam tyloxycarbonyl or tert.-butoxycarbonyl. In this connection, starting compounds can be employed, in general, which contain on the amino residue R acyl residues readily to be split off in acidic media. Optionally, when conducting this mode of reaction, it is also possible to convert an amino group contained in the side chain R into a hydroxy group.

The following compounds are set forth as examples for the starting compounds Vll:

Z-methyl-3-hydroxy-4-amino-methyl-5-methylthiomethyl-pyridine, 2-rnethyl-3-hydroxy-4-aminomethyl S-carbethoxymethyl-pyridine, Z-methyl-3-hydroxy-4-(o-nitrophenylsulfenyl)- aminomethyl-S-aminoethylthiomethyl-pyridine, 2-methyl3-hydroxy-4-( l -adamantyloxycarbonyl)- amino-5 -acetyl-thiomethyl-pyridine, 2-methyl-3-hydroxy-4-tritylaminomethyl-5-(/3- carboxy-B-amino)-ethylthiomethyl-pyridine, and 2-methyl-3-hydroxy-4-( t-butyloxycarbonyl aminomethyl-S-chlroethylthiomethyl-pyridine. The starting compounds of Formula Vll are obtainable, for instance, by reacting pyridoxamine with 66 percent hydrobromic acid to form bromopyridoxamine, and further reacting the latter with corresponding halogenides or azides, such as l-adamantyloxycarbonyl chloride, trityl chloride and vo-nitro-sulfenyl chloride in an aqueous solution, or e.g.,

with t-butyloxycarbonylazide in, for example, 50 percent aqueous dioxane, to the corresponding 5'- bromopyridoxamine substituted in the amino group.

This latter compound can then be converted into the desired starting products Vll by thioalkylation or thioacylation.

f. It is also possible to prepare a compound of Formula I from a S-thiomethyl derivative of the abovementioned Formula III herein X H oran alkali or alkaline earth metal cation, by addition to an alkene or alkyne optionally substituted by halogen, OH, lower alkoxy, SH, lower alkylthio, optionally functionally modified carboxy and/or 1 I If desired, the compounds ii! an also be added to alkenes or alkynes containing undesired substituents.

The undesired substituents can be split off subsequently, or they can be converted into desired substitu- CHIS.

Preferably, in this mode of operation of the process according to the invention, the mercapto compounds III are added to unsaturated carbonyl compounds; the 'caronyl residue can, if desired, be removed later on, or

converted into a desired substituent. Particularly suitable for the addition reaction are a; B-unsaturated carboxylic acids, especially lower a, B-unsaturated carboxylic acids or the functional derivatives thereof, e.g., the esters or nitriles, such as acrylic acid, methyl acrylate and ethyl acrylate, acrylonitrile, methacrylic acid, methacrylate, methacrylic acid nitrile, crotonic acid, crotonitrile. Furthermore, other ctfi-unsaturated carbonyl compounds can also be employed, for example, a,B-unsaturated ketones, such as methylvinyl ketone or a,B-unsaturated aldehydes, such as acrolein, as the addition components.

Additionally, the mercapto compounds can also be added to acetylenically unsaturated hydrocarbons which are optionally substituted in a functionally suitable manner, e.g., acetylene derivatives, such as pro pargyl aldehyde, propargyl alcohol, propargyl halogenides, particularly propargyl chloride and bromide, vinyl acetylene, propargylic acid and the functional derivatives of propargylic acid.

Further addition components which can be employed in conjunction'with the mercapto compounds III are also Schiff bases, especially Schiff bases of lower aliphatic aldehydes and lower primary or secondary alkylamines.

Undesired substituents in the alkenes or alkynes employed for the addition reaction can be removed after the addition process, or they can be converted into desirable substituents as described below under (g).

The addition reactions of the mercapto compounds I]! to alkenes or alkynes are conducted in accordance with the processes set forth in Houben-Weyl, ed. cit.,

4th Edition, Vol. 9, (1955), pp. 120-133. When employing this type of operation, compounds of Formula l are obtained wherein R represents a substituted alkyl residue, optionally defined as in Formula 1, but containing in the present case at least 2 carbon atoms.

(g) Compounds of Formula I or the salts thereof can also be produced by removing, in the residue R undesired substituents or converting the latter into desired substituents and/or by hydrogenating undersired C=C double bonds or C E C triple bonds. Furthermore, it is possible to introduce into a residue R any desired substituents and/or C-C unsaturated bonds which may not as yet be present therein.

g For example, undesired halogen, hydroxy or carbonyl groups present in the residue R can be split off or reduced to H.

The process of cleaving off an undesired halogen,

e.g., the conversion of a compound of Formula I containing the residue R CH -halogen, particularly palladium). The conditions for this reduction are described in Weygand-Hilgetag, ed. cit., pp. 169-172,F. Zymalkowski, Katalytische Hydrierungen im Organisch-Chemischen Laboratorium [Catalytic Hydrogenations in the Organic-Chemical Laboratory], F.

Enke Publishers, Stuttgart, 1965, pp. 158-161; Organic syntheses, Coll. Vol. 4, p. 509, lntersciene Publishers, New York (1963); N.G. Gaylord, Reductions with Complex Metal Hydrides, lnterscience Publishers, New York (1965), pp. 889-917; A. Hajos Komplexe Hydride (Complex Hydrides), VEB Deutscher Verlag der Wissenschaften (publisher), Berlin, 1966, pp. 219 and 276.

An undesired hydroxy group in the residue R, can be removed by reduction with base/metals/acids, particularly with zinc/acetic acid or dilute hydrochloric acid, or also catalytically, for instance under the conditions set forth in R.L. Augustine, Catalytic Hydrogenatioml Techniques and Applications in Organic Symthesis,l Edward Arnold Publishers, London (1965), pp.% 135-139; and Weygand-Hilgetag, ed. cit., pp. 177-178.;

If desired, the hydroxy group can also be removed? after a preceding esterification with a sulfonic acid, particularly p-toluenesulfonic acid. For instance, the conditions can be employed herein as described in L.F. Fieser and M. Fieser, Reagents for Organic Symthesis, p. 1032, J. Wiley & Sons, Inc., New York (1967).

In case an undesired carbonyl group is present in the residue R particularly as a component of an aldehyde or keto grouping such carbonyl group can be reduced in accordance with the methods customary for the reduction of carbonyl groups. A carbonyl group can be reduced, for example, in accordance with the following methods: catalytically, e.g., with platinum oxide or Raney nickel, sodium/absolute alcohol; zinc dust in an acidic or alkaline solution, and complex metal hydrides particularly .lithium aluminum hydride in the presence of aluminum chloride. The conditions for this reducing process are described, for example, in Weygand-Hilgetag, ed. cit., pp. 178-181; F. Zymalkowski, Katalytische Hydrierungen im Organisch Chemischen Laboratorium, ed. cit., pp. 158-161; R.L. Augustine, Catalytic Hydrogenation, Techniques and Applications in Organic Synthesis, ed. cit., pp. 135-139; and A. Hajos, Komplexe Hydride, ed.cit. (1966), PP 295-306.

The preferred reducing agent is lithium aluminum hydride-aluminum chloride. Optionally, organotin hydrides can also be employed as the reducing agents, particularly diphenyl tin dihydride and di-n-butyl tin dihydride, as well as diphenyl silane and a trialkyl borane. The conditions for this reduction are described for instance, in A. l-lajos, Komplexe Hydride, ed. cit., pp. 288-290. 4

5 The addition of hydrogen to undesired unsaturated CC bonds in the side chain can be accomplished with the aid of the catalysts conventionally used for hydrogenation purposes. The more detailed conditions for these reactions are set forth in R.L. Augustine, Catalytic Hydrogenation, ed.cit., pp.135-139, and F. Zymalkowski, Katalytische Hydrierungen im Organisch- Chemischen Laboratoriam, ed. cit., pp. 158-161.

Likewise, it is possible, if desired, to saturate with hydrogen any C i C triple bond present in the residue R either to the C=C double bond or to the CC single bond. The conditions therefore are described in greater detail in the above-cited works of R.L. Augustine, pp. 135-139, and F. Zymalkowski, pp. 158-161.

Finally, it is also possible to employ chemical reducing agents for the addition of hydrogen to the undesired unsaturated bonds, e.g., base metals, particularly sodium in alcohols, sodiumor aluminum-amalgam in wa- 'ter, alkali or alkaline earth metals in liquid ammonia,

with respect to their use in NO. Gaylord and Hajos, ed.

cit., as well as, in particular, borohydrides, the operating guidelines for these being described in H.C. Brown, Hydroboration, New York (1962).

g, In the side chain R of a pyridine derivative 1, it is also possible, if desired, to introduce CC unsaturated bonds by means of the methods conventional for the formation of C=C double bonds and/or C E C tri ple bonds.

For example, a C=C bond can be introduced into the residue R, containing an undesired hydroxy or alkoxy or halogen group, respectively, by splitting off water, alcohol or a hydrohalic acid, respectively from a compound of Formula 1. If two identical undesired substitucuts are present on neighboring carbon atoms of the side chain R at C 1 C- bond can be introduced into the side chain R, by splitting off these undesired substituents.

When splitting off water, the reaction is generally conducted in an aqueous solution with the addition of sulfuric acid, potassium hydrogen sulfate, zinc chloride, phosphorus pentoxide, boric acid, oxalic acid, formic acid, acetyl chloride, Grignard reagent, or iodine, and optionally at elevated temperatures. The more detailed conditions under which these reactions can be conducted are set out, for instance, in Weygandl-lilgetag, ed.cit., pp. 782-788.

The removal of the components of a hydrohalic acid is accomplished by the use of inorganic or organic bases such as, e.g., anhydrous alkali alcoholates, solid alkali hydroxides, solutions of alkali hydroxides in water or organic solvents, alkali salts of weak acids, as well as organic bases,such as pyridine, aniline, dimethylaniline and quinoline. The conditions employed in this connection are described, for example, in Weygand-Hilgetag, ed. cit., pp. 788-790.

If the residue R contains an other grouping in a compound of Formula I, e.g., an acetal or ketal, alcohol can be split off, with the formation of a C=C double bond, by the use of specific acidic reactants, e.g., percent phosphoric acid. The conditions which can be employed herein are described in greater detail, for example, in Organikum, 2nd Edition, VEB Deutscher 0 Verlag der Wissenschaften (publishers), Berlin (1963 pp. 137-203, or in Annalen der Chemie," Vol. 656, pp. 97-102 (1962).

It is also possible to obtain C=C double bonds in a side chain R by splitting off thioethers from a tertiary sulfonium compound in accordance with conventional methods (see, in this connection, S. Patai, The Chemistry of Alkenes, lnterscience Publishers, New York (1964), pp. et seq.), particularly by splitting off, for instance, dimethyl sulfide from tertiary sulfonium salts, the third branch of which is the residue R As an example, the following reaction is set forth:

CHgRu C HgRg R5 1 GH7-S-CH=CH Hz wherein R R and W have the above-indicated meanings, and in place of CH -CH,, there can also be present a longer-chain alkylene residue.

Finally, a desired double bond in the side chain R, can also be introduced by a condensation reaction wherein a compound 1 with a reactive functional group suitable for the conductance of the condensation reaction reacts with a second compound likewise suitable for the condensation reaction, with the formation of a double bond and simultaneous lengthening of the chain. Suitable for this purpose are primarily aldol, Knoevenagel and Wittig reactions. As the starting substances, compounds of Formula I are employed which, however, contain an undesired C=O group in the side chain R The reaction conditions which can be employed in this connection are described more clearly in: Houben- Weyl, ed.cit., Vol. 7/1 (1954), pp. 76-92, regarding the conductance of the aldol condensation; in G. JONES, The Knoevenagel Condensation in: Organic Reactions, Vol. 15, published by AC. Cope, J. Wiley & Sons, New York, (1967), for the conductance of the Knoevenagel condensation; and in Johnson, Ylid Chemistry, Academic Press, New York (1965) for the conductance of the Wittig reaction.

g Halogen residues can be introduced into the side chain R in accordance with this invention, by the addition of hydrogen halide or halogen to C-C unsaturated bonds, or by the addition of hypohalogenite, there being introduced an OH group together with the halogen, or by halogenation of undesired OH OR C=O groups.

The addition of chlorine and bromine to a compound I with an unsaturated side chain R is preferably conducted in an inert solvent, particularly carbon tetrachloride or chloroform, by introducing the stoichiometric amount of chlorine gas or adding the stoichiometric quantity of bromine in the same solvent. The condtions under which the reaction can be conducted are described in greater detail, for instance, in Houben- Weyl, ed. cit., Vol. 5/3 (1962), pp. 529-551, and Vol.

5/4 (1960), pp.38-100 The conditions for the addition of hypohalic acids are found in Houben Weyl, ed.-

cit., Vol. 5/3 (l962),pp. 760-780 and V]. /4 (1960),

pp. 133-141 or p. 54. The operating conditions for the addition of hydrogen halides are described in greater detail in Houben-Weyl, ed. cit., Vol. 5/3 (1962), pp.

811-829 and Vol. 5/4 (1960), pp. 102-132 and 535. Halogen residues can also be introduced by the halogenation of compounds of Formula 1 containing undesired OH OR C=O groups in the residue R,, by substituting the OH or the oxygen of the C=O group against halogen. For such substitution reactions, a number of reactants can be employed, such as, for example, for the substitution of OH by C1, sulfur halogenides, such as disulfur dichloride, sulfur dichloride, thionyl chloride, chlorine compounds of phosphorus and nitrogen,

such as phosporus pentachloride, phosphorus trichloride, phosphorus oxychloride, nitrosyl chloride, nitryl chloride, as well as, finally, several other inorganic and organic chlorine compounds. This reaction is described in greater detail, for example, in Houben-Weyl, ed.cit., Vol. 5/3 pp. 564 et seq., for chlorine and in Vol. 5/4 of the aforementioned reference, pp. 610-629, 638 and 361-409, for bromine and iodine, as well as in Weygand-Hilgetag, ed. cit., pp. 298-323,

The conversion of undesired carbonyl groups into gemdihalogenides (e.g., 1,1-dihalogenides), particularly =CC1, and =CBr is effected by the activity of inorganic acid halogenides, particularly phosphorus halogenides, e.g., PG; or PBr The conditions under which the process can be conducted are explained, for example, in Weygand-Hilgetag, ed. cit., pp. 334-335, or in Houben-Weyl, ed.cit., Vol. 5/3, p. 912 and Vol. 514, p. 434.

g,. A hydroxy group can be introduced into the residue R of a compound 1 by the addition of water to undesired C-C unsaturated bonds or by the reduction of C=O groups or free or esterified COOl-l groups or of an epoxide group, or by the effect of H-acidic compounds on an epoxide bond.

The introduction of a hydroxyl group by the addition of water to C=C double bonds and C E C triple bonds can be effected, for example, under the conditions described in greater detail in Weygand-l-lilgetag, ed. cit., pp. 359-365, as well as in BA. Krenzel, Fortschritte der Chemie [Advances in Chemistry] (Russ.) 201759-775 (1951); RA. Asinger, Chemie und Technologie der Monoolefine [Chemistry and Technology of the Monoolefins], Akademie Publishers, Berlin (1957); RA. Raphael, Acetylenic Compounds in Organic Synthesis, Butterworths, London (1955); and F. Bohlmann, Struktur und Reaktionsfahigkeit der Acetylenbindung [Structure and Reactivity of the Acetylene Bond], Angew. Chemie (Applied Chemistry) 69,82-86 (1957).

Furthermore, hydroxy groups in the residue R can be formed by the reduction of C=O groups. Suitable reducing agents are the reactants of the Meerwein- Ponndorf-Verley reaction, i.e., aluminum triisopropylate in absolute isopropyl alcohol, as well as complex metal hydrides, particularly LiAlH, and NaBH.,, and base metals together with acids, primarily zinc in acetic acid, as well as, finally, catalytically activated hydrogen, e.g., with the use of platinum oxide, platinum black and other conventional catalysts. The conditions under which the process can be conducted are set out in more detail in Weygand-Hilgetag, ed. cit., pp. 154-169, as well as Neuere Methoden der Praparativen Organischen Chemie, edited by W. Forest, Vol. 1, pp. 137-154, Chemie Publishers, Weinheim (Bergstrasse), 3rd Edition, 1949 (Meerwein-Ponndorf- Verley reductions); in A. Hajos, ed. cit., pp. 126, 230,

240 and 279', N.G. Gaylord,ed. cit., pp. 107-124 (reductions with complex hydrides); and also in F. Zylmalkowski, ed.cit., pp. 91-103; and R.L. Augustine,- ed.cit., pp. -88 (catalytic hydrogenations of the C=O ployed. The conditions that can be utilized in this connection are described in more detail in Organic Symtheses, ed. cit., Coll. Vol. II, pp. 154 and 372, as wellas Coll. Vol. 111, p. 671, and in N.G. Gaylord, ed.cit., pp. 322-638, as well as A. Hajos, ed. cit., pp. 158, 258,, 285, 298, 310 and 349. Also suitable is a process utilized for the reduction of carboxy groups to OH groups, i.e., catalytic hydrogenation, in particular with copperchromium oxides (copper chromite) or Raney nickel. In this connection, the process can be conducted according to the conditions set forth in Weygand- Hilgetag, ed. cit., pp. 184-187.

It is also possible to introduce into the residue R of a compound I an OH group by the reduction of an epoxide grouping in the residue R e.g., with base metals and dilute acids, but especially with complex metal hydrides. More elaborate details for conducting such reactions are described in N.G. Gaylord, ed. cit., pp. 646-673 and A. Hajos, ed.cit., pp. 149-155. It is further possible to split the epoxide ring by compounds containing active hydrogen whereby the ring opening results, with a lengthening of the side chain, in the compounds of this invention having an OH-substituted residue R If desired, it is possible during this reaction to additionally introduce other functional groups into the residue R at the same time.

For example, by the effect of an alcohol on an undesired epoxide bond in the residue R of a compound I, an OR group is formed with splitting of the epoxide ring, with the simultaneous introduction of an alkoxy residue into the substituent R Additional suitable reactants for the formation of a hydroxy group from an epoxide bond are mercaptans, amines, carboxylic acids or Grignard reagents.

g An alkoxy group can be introduced into the residue R of a compound I by the addition of an alcohol to an undesired C=C double bond or C E C triple bond in the residue R in this connection, the conditions are utilized set forth in greater detail in Weygand-Hilgetag, ed. cit., pp. 372-376. Optionally, it is also possible to convert a hydroxy group already present in the residue R into an alkoxy group, by alkylation under the conditions described in mode of operation (b) above or in Houben-Weyl, ed. cit., Vol. 6/3, pp. 10-49.

g,,. An Sl-I or S-alkyl group can be introduced into the residue R in a compound of the above Formula I by addition of hydrogen sulfide or a mercaptan to an undesired CC double or triple bond contained in the residue R or by reduction of an undesired sulfuroxygen function contained in the residue R this mode of operation leading to 81-! groups. More detailed conditions for the addition reaction are described in greater detail in the process (f) above, and in Houben- Weyl, ed. cit., Vol. 9. (1955), pp. 120-134.

In the reduction of an undesired sulfur-oxygen function, i.e., a higher oxidation stage of the sulfur in the residue R,, a starting compound is selected, for example, of Formula I. but which contains an S0 11 group, particularly in the esterified form; sulfonic acid halogenide or anhydride residues; or, for instance, a sulfinic acid group SO I-I. Suitable reducing agents include base metals with acids, and especially complex metal hydrides, the use of which is more specifically described in N .G. Gaylord, ed. cit., pp. 851-875.

g,. An optionally alkylated amino group can be introduced into the residue R by treating a compound of Formula 1 containing undesired halogen or OH in the residue R with ammonia or hexamethylenetetramine or an amine; or by addition of amino compounds to undesired C--C unsaturated bonds; or by the reduction of undesired residues CN, NO- =NOl-1, Nl-lNl-l -NO, in the residue R,.

In the reaction with ammonia, hexamethylenetetramine or primary or secondary amines, the conventional conditions of an N-alkylation are observed. Preferably, compounds of Formula I are employed as the starting materials which are substituted in the residue R, by I or also by Br. When introducing an unsubstituted N H, group, an at least ten-fold excess of ammo nia is employed, and the solvents used in this connection are generally alcohols, particularly methanol or ethanol.

The substitution of an undesired halogen by an amino group in the residue R of a compound 1 can also be accomplished with the aid of the Gabriel method with the use of potassium phthalimide. A detailed description of the method used herein is found in Weygand-Hilgetag, ed. cit., pp. 516-529, as well as in Houben-Weyl, ed. cit., V01. 11/1 (1955), pp. 24-96.

Furthermore, it is possible, in the compounds of Formula I in the residue R to substitute undesired hydroxy groups by amino, alkylamino or dialkylamino groups. In this connection, conditions are employed which are set out in detail in Houben-Weyl, ed. cit., Vol. 11/1 (l955),pp. 108-236.

If the residue R contains undesired CC unsaturated bonds, particularly in conjugation with respect to activating groups, such as, e.g., the formyl, keto, sulfone, nitro or carbalkoxy group, then it is also possible to produce the amino groups in the residue R by the addition to such unsaturated bonds, of suitable components, e.g., ammonia, primary and secondary amines, as well as those of a cyclic character, such as, e.g., piperidine, piperazine or ethylenimine, to these CC unsaturated bonds. The more specific conditions under which these reactions are carried out are described in greater detail in Houben-Weyl, ed.cit., Vol. 1 1/1 (1955) pp. 267-341.

Furthermore, an NR R group in the residue R can be obtained by reducing a compound of Formula' I containing additionally in the residue R undesired groups reducible to amino, alkylamino or dialkylamino residues, especially CN, NO NO, =N-O1-I or Nl-lNl-I groups. In this connection, reducing agents are employed which are conventionally utilized for such reduction processes, in particular sodium amalgam, sodium in alcohol, other base metals, e.g., zinc, with acids, sodium dithionite or complex metal hydrides, more detail being given in Houben-Weyl, ed.- cit., Vol. ll/l, pp. 341-730.

g;,. A carboxy group can be introduced into the residue R of a compound 1 by oxidation of undesired substituents, particularly formyl groups and primary alcoholic hydroxy groups, or by hydrolysis of a functionally modified COOl-I group, or by other synthesis methods conventional for the formation of COOI-I.

Thus, it is possible to introduce a carboxy group into the residue R by oxidizing suitable undesired substituents in the residue R starting with compounds optionally protected in the 3- and 4-positions of the pyridine 5 ring. All conventional oxidizing agents can be employed, more detailed conditions being described in Weygand-I-Iilgetag, ed. cit., pp. 405-407, and in Houben-Weyl, ed.cit., Vol. 8(1952), pp. 407-414.

lf the residue R, already contains an undesired functionally modified carboxy group, it is possible to liberate therefrom a carboxy group by the use of saponifying agents. Functional derivatives are, in particular, acid nitriles, esters, amides, hydrazides, amidines, the acid halogenides and the hydroxamic acids, and reaction conditions for these conversion reactions are described in greater detail in Houben-Weyl, ed. cit., Vol. 8 (1952), pp. 418-433.

Carboxy groups can also be introduced into the side chain by aceto-ethyl acetate and malonic acid syntheses, by the conversion of ketones; by splitting nitro compounds, by carbon chain formation; and rearrangement reactions, as described in greater detail in Houben-Weyl, ed. cit., Vol. 8 (1952), pp. 433-462.

g,. If desired, free or functionally modified carboxy groups in the residue R of a compound I can be further functionally modified.

In particular, free COOH groups or carboxylic acid halogenides can be converted into esters, amides, anhydrides or other functional derivatives. It is also possible to convert esters into amides.

For the esterification of a free COOH group in the residue R of a compound I, known processes are employed, including but not limited to, esterification with diazoalkanes, or reaction with alkali alcoholates (Williamson symthesis), additional details being given in Houben-Weyl, ed.cit., Vol. 8 (1952), pp. 508-628.

For amidation, or for the introduction of the other N-derivatives, there are employed reactive functional derivatives of the carboxyl group in the residue R primarily the esters, anhydrides and halogenides. The conditions under which it is possible to operate when preparing such functional N-derivatives of the carboxy group are described specifically in Houben-Weyl, ed.- cit., Vol. 8 (1952), pp. 653-706.

When the products obtained by the above-described processes (b) (g) have the hydroxy residues R and R still protected, these protective groups are split off subsequent to the main process stages (b) to (g). For liberating these protected hydroxy groups, the conditions are employed as described in mode of operation (a). In this connection, the acidic and/or alkaline agents used for splitting off the protective groups are employed preferably in diluted form.

It is further possible to optionally convert compounds of Formula I wherein R represents S into the corresponding final products containing the residue by treatment with oxidation agents conventionally employed for the conversion of thioethers into sulfoxides. Preferred oxidation agents are hydrogen peroxide, sodium metaperiodate, peracids, such as monoperphthalic acid or chromium trioxide in acids, e.g., in 75 percent acetic acid, or t-butyl hypochlorite. The oxidation is suitably conducted under the following condi- 50 tions:

The compounds I wherein R, S are dissolved in glacial acetic acid and allowed to stand with the stoichio-i metric amount of 30 percent H 0 several hours at 0 C or also at room temperature. The oxidation of compounds I wherein R S with sodium periodate is advantageously conducted in a water/methanol mixture at room temperature. For the oxidation with peracids, temperatures are employed ranging between -20 C and +20 C, and preferred solvents used are acetone or chloroform. The conditions under which the oxidation with t-butyl hypochlorite can be conducted are described in greater detail in J. Org. Chem., Vol. 32 (10), 31 l l (1967).

A final product of Formula I can be converted into the acid addition salt thereof by means of an acid in the usual manner. For this reaction, those acids are suitable which yield physiologically acceptable salts. Thus, suitable acids are, for example, organic and inorganic acids, such as, e.g., aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monoor polybasic carboxylic or sulfonic acids, including but not limited to, formic, acetic, propionic, pivalic, diethylacetic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic acid; aminocarboxylic acids; sulfamic, benzoic, salicylic, phenylpropionic, citric, gluconic, ascorbic, isonicotinic, methanesulfonic,ethanedisulfonic, S-hydroxyethanesulfonic, p-toluenesulfonic acid; naphthalene-monoand -disulfonic acids, sulfuric acid, or hydrobromic acid, or phosphoric acids, such as orthophosphoric acid, etc. In this connection, mineral acids are preferred, such as hydrochloric acid or sulfuric acid.

It is also possible, if desired, to convert compounds of Formula 1 into the quaternary ammonium salts thereof and/or the tertiary sulfonium salts thereof. This conversion is conducted with conventional alkylating agents (called in the description below N,S- dialkylation" and N- or S-monoalkylation, respectively). The alkylation can be conducted, for example, with alkyl halogenides, preferably with lower alkyl halogenides, in particular the iodides, such as methyl iodide, ethyl iodide, propyl iodide, allyl iodide, or also with benzyl iodide. If desired, it is also possible to subsequently replace an undesired halogenide ion, e.g., I by a desired halogenide ion, e.g., Cl or Br" by way of ion exchange techniques well known in the art. Sulfuric acid esters or sulfonic acid esters are likewise suitable for the reaction.

The formation of quaternary ammonium or tertiary sulfonium salts can be conducted in the optional presence of a solvent. Especially suitable solvents are those having a high dielectric constant, such as chloroform or nitro compounds, such as nitrobenzene or nitromethane, or cyano compounds, such as acetonitrile, or if desired, benzyl alcohol. Though the reactions are normally conducted at room temperature, higher temperatures can also be employed.

The rapidly reacting agents used for producing quaternary compounds, for example the alkyl iodides, are suitably added in an equimolar proportion; whereas, less reactive alkylating agents, for example an alkyl chloride, are advantageously employed in excess.

if desired, it is also possible to alkylate selectively. For example, the N-alkylation of the compounds of Formula I can also be accomplished with less reactive alkylating agents.

Generally, for the production of quaternary ammonium and/or tertiary sulfonium slats of the compounds of Formula I, alkylating agents are preferred which contain a lower alkyl residue, particularly a methyl residue. By reacting a compound I wherein R S and R CH with methyl iodide, for example, the compound 2-methyl-3-hydroxy-4-hydroxymethyl-5methylthiomethyl-pyridinium iodide is obtained.

Aside from the formation of the above salts, a compound of Formula I can also be liberated from a corresponding ammonium and/or sulfonium salt. This reaction is effected by the addition of nucleophilic reactants, particularly bases, in an inert solvent, or by the addition of a basic-reacting solvent.

As suitable nucleophilic reactants, bases are preferred, including but not limited to: alkali mercaptides, such as sodium or potassium mercaptides which can optionally be substituted by a hydrocarbon residue, e.g., methyl, ethyl or benzyl, sodium or potassium mercaptide; alkali thiosulfates, such as sodium or potassium thiosulfates; ammonia or amines, particularly aliphatic amines liquid at room temperature, such as ethyl, propyl or benzylamine, and especially ethanolamine. The reaction can be conducted in the optional presence of an inert solvent, including but not limited to, alcohols, particularly lower alcohols, such as methanol, ethanol, propanol, isopropanol; or acetone; or methyl ethyl ketone.

Further details of reaction conditions are found, for example, in l-louben-Weyl, ed.cit., Vol. 1111 (1957), pp. 966-991, and in Chemische Berichte [Chemical -Reports], Vol. 90, 305 and 403 (1957).

Similarly, it is also possible to liberate a compound of Formula I from an undesired acid addition salt by treatment with an alkaline reagent, especially an alkali hydroxide, such as sodium or potassium hydroxide, or with an alkaline-reacting salt, such as an alkali carbonate, e.g., sodium or potassium carbonate. If desired,

,this liberated compound of Formula I can then again be converted into another desired acid addition salt. The compounds of Formula I cam be employed in a mixture with conventional pharmaceutical excipients and, if desired, together with other active substances. Carrier substances can be such organic or inorganic substances suitable for parenteral, enteral, or topical application, and which, of course, do not deleteriously react with the novel compounds, such as, for example, water, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, vaseline, cholesterol, etc.

For parenteral application, particularly suitable are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Ampoules are convenient unit dosages.

For enteral application, particularly suitable are tablets or dragees which are also characterized by talc and/or a carbohydrate carrier or binder or the like, the carbohydrate carrier being preferably lactose and/or corn starch and/or potato starch. A syrup or the like can also be used wherein a sweetened vehicle is employed.

For topical application, viscous to semi-solid forms are used such as liniments, salves, or creams, which are, if desired, sterilized, or mixed with auxiliary agents, such as preservatives, stabilizers, or wetting agents, or salts for influencing the osmotic pressure, or with buffer substances.

The compounds of this invention are administered to animals, e.g., mammals, in therapeutically effective amounts, e.g., amounts effective to increase animal to]- erance to oxygen defiency, in preferred dosages of l 500 mg per dosage unit, the dosage per kg ratio being about 0.1 to 50 mg per kg. In general, the amount of carrier varies from 1 5,000 mg and the preferred dosage is about 100 mg active compound.

Aside from the details of how to use the compounds of this invention, as previously set forth, they can be used, generally speaking, in the same manner as the known cysteine, used as protective substance against high intensity radiation or the known bis-(3-hydroxy-4- hydroxymethyl-Z-methyl-pyridyl-( 5 )-methyl )-disulfide used as effective compound for curing cerebral disfunctions.

The protective effect against high intensity radiation may be evaluated with the method, published in Strahlentherapie," Volume 107, (1958) page 121-126. The curing effect for combatting cerebral disfunctions maybe evaluated for example with the methods published in Medicine Experimentalis, Vol. 7, (1962) pages 144 154 and Deutsche Zeitschrift fur Nervenheilkunde, Vol. 188, (1966), p. 200 209.

The administered dosages of the compounds according to the invention are about the same as those which are generally administered for cysteine or bis-(3- hydroxy-4-hydroxymethyl-2-methyl-pyridyl-( 5 methyl)-disulfide.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative, of the remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 1 1 g. of 5-hydroxy-4-hydroxymethyl-3- mercaptomethyl--methyl-pyridine hydrochloride is added to a solution of 6.2 g. KOl-l in ml of methanol, and mixed with 7 g. of methyl iodide. After allowing the reaction solution to .stand overnight, it is concentrated, mixed with water, and extracted with ethyl acetate. The solution is dried over Na SO and the solvent is evaporated. The residue, consisting of 5- hydroxy-4-hydroxymethyl-3-methylthiomethyl-6- methyl-pyridine after recrystallization from alcohol, melts at C. Yield: 8.7 g. of hydrochloride, m.p. 155 C. (decomposition) EXAMPLE 2 In a solution of 1,000 ml. of water and 250 ml. of 2N NaOH, 110 g. of 5-hydroxy-4-hydroxymethyl-3- mercaptomethyl-G-methylpyridine hydrochloride is dissolved and, under stirring, 63 g. of dimethyl sulfate and 250 ml. of 2N NaOl-l are added dropwise at the same time so that the pH of the solution is between 7 and 7.5. The temperature of the solution ranges between 20 and 25 C. After 5 hours of agitation, the precipitated 5-hydroxy-4-hydroxymethyl-3-methylthiomethyl--methyl-pyridine is vacuum filtered and, after being dried in a desiccator, is treated with alcoholic HCl. The thus-precipitated hydrochloride is vacuum filtered and recrystallized from alcohol/ether; m.p. l54-155 C. (decomposition).

EXAMPLE 3 20 g. of methyl p-toluenesulfonate is dissolved in 220 ml. of methanol containing 8 g. of NaOH, then mixed with 22 g. of 5-hydroxy-4-hydroxymethyl-3- mercaptomethyl-o-methyl-pyridine hydrochloride and allowed to stand for 12 hours at room temperature. The solution is concentrated under vacuum, mixed with water, and extracted with ethyl acetate. The solution is dried over Na SO and the residue obtained after the solvent has been evaporated is treated with alcoholic ,panol, mercaptomethyl6-methyl-pyridine and 7 g. of n-butyl bromide are added. After refluxing the reaction mixhydroxymethyl-6-methyl-pyridine added 37.5 g.

31 i-lCl. The thus-precipitated -hydroxy-4- hydroxymethyl-3-methylthiomethyl-6-methyl-pyridine hydrochloride is vacuum filtered and recrystallized from alcohol/ether; m.p. 154-155 C (decomposition).

EXAMPLE 4 To a solution of sodium mercaptide in methanol (produced by the introduction of CH SH into a solution of 2.3 g. of sodium in 40 ml of methanol), a solution of l8.7 g. of 3chioromethyl-S-hydroxy-4- hydroxymethyl-o-methyl-pyridine in 200 ml of methanol is slowly added and then refluxed for one-half hour. The NaCl which separates is vacuum filtered, and the filtrate is concentrated by evaporation. The residue is treated with alcoholic HC], and the thus-precipitated 5-hydroxy-4-hydroxymethyl-3methylthiomethyl-G- methyl-pyridine hydrochloride is vacuum filtered; m.p. l53154 C (decomposition).

EXAMPLE 5 A solution of 0.5 g. of sodium in 50 ml of isopropanol ;is mixed with 2.3 g. of dimethyl aminoethyl mercaptan and thereafter with 5 g. of 3-bromomethyl-5-hydroxy- 4hydroxymethyl--methylpyridine. After heating the reaction mixture for 1 hour to 60 C, the thusprecipitated NaBr is vacuum filtered, and HC! is introduced into the filtrate until a weakly acidic reaction is obtained. After adding 5 ml. of ether, the 3- dimethylaminoethylthiomethyl-5-hydroxy-4- hydroxymethyl-6-methyl-pyridine dihydrochloride precipitates. The substance is vacuum filtered and recrystallized from methanol/ether; m.p. 200 C (decomposi- -tion).

EXAMPLE 6 To a solution of 1.2 g. of sodium in 100 m]. of isopro- 9.2 g. of 5hydroxy-4-hydroxymethyl-3- ture for 1% hours, it is vacuum filtered from the precipitated NaBr, and HCl is introduced into the filtrate. The thus-precipitated 3-n-butylthiomethyl-5 hydroxy-4- hydrochloride is then vacuum filtered and redissolved from alcohol/ether; m.p. 124 C.

EXAMPLE 7 A solution of 35 g. of cysteine HCI H O in 50 ml of water is heated to 40 C. Simultaneously, there are of 3chloromethyl-Shydroxy-4- hydroxymethyl-o-methyl-pyridine in batches and a solution of 22.4 g. of KOH in 30 ml. of water. During this reaction step, the temperature increases to 68 C. After 40 minutes, the reaction mixture is cooled, and the thus-precipitated residue is vacuum filtered. For purification purposes, this precipitate is dissolved in 80 ml of 2N HCl and the pH of the solution is adjusted to 5.5 by means of 2N NaOH. The S-[5-hydroxy-4- hydroxymethyl-6methyl-pyridyl-(3)-methyl]-cysteine precipitated overnight is vacuum filtered, washed with water and methanol, and dried in a desiccator; m.p. 230 C (decomposition).

EXAMPLE 8 A solution of 22 g. of 5hydroxy-4-hydroxymethyl-3- mercaptomethyl--methyl-pyridine hydrochloride in 20 ml of water is mixed with 10 ml of 35 percent form- 32 aldehyde solution. The 5hydroxy-4-hydroxymethyl-3- hydroxymethylthiomethyl-6-methyl-pyridine hydrochloride precipitated after allowing the reaction mixture to stand for 12 hours is vacuum filtered and recrystallized from methanol; m.p. 157 C.

EXAMPLE 9 Analogously to Example 6, S-[5-hydroxy-4- hydroxymethyl-fi-methyl-pyridyl-( 3 )-methyl 1- thioacetic acid ethyl ester is produced by reacting 5- hydroxy-4-hydroxymethyl-3mercaptomethyl-6- methyl-pyridine with ethyl chloroacetate; m.p. 96 C (alcohol); hydrochloride, m.p. 175 C (alcohol/ether).

EXAMPLE l0 Analogously to Example I, 3-allythiomethyl-5- hydroxy-4-hydroxymethyl-6-methyl-pyridine is prepared by reacting 5hydroxy-4-hydroxymethyl3- mercaptomethyl-6-methylpyridine hydrochloride with allyl bromide; m.p. 111 C (ethyl acetate/hexane); hydrochloride, m.p. 136 C.

EXAMPLE I l Analogously to Example I, 5-hydr0xy-4- hydroxymethyl-6-rnethy]3-propargylthiomethylpyridine is produced by reacting 5-hydroxy-4- hydroxymethyl-3mercaptomethyl--methyl-pyridine with propargyl chloride; m.p. 140 C (ethyl acetate/- hexane); hydrochloride, m.p. C.

EXAMPLE 12 1.4 g. of 5hydroxy-4-hydroxymethyl-3- methylthiomethyl-6-methyl-pyridine hydrochloride is allowed to stand in 30 ml of glacial acetic acid with 0.8 ml of 30 percent H 0 at room temperature for 48 hours. The solvent is evaporated under vacuum, and the thus-precipitated 5hydroxy-4-hydroxymethyl-3- methylsulfinylmethyl--methyl-pyridine hydrochloride is recrystallized from alcohol/ether; m.p. 179 C.

EXAMPLE 1 3 To a solution of 23.5 g. of sodium metaperiodate in 200 ml of water cooled to 0 C is added 21 g. of 3- ethylthiomethyl-Shydroxy-4-hydroxymethyl-6-methylpyridine in 50 ml of methanol. The precipitated substance is vacuum filtered, and the filtrate extracted with ethyl acetate. The solvent is dried over Na SO and evaporated under vacuum. The residue is treated with alcoholic BC]; the thus-precipitated 3- ethylsulfinylmethyl-Shydroxy-4-hydroxymethyl-6- methyl-pyridine hydrochloride is vacuum filtered and recrystallized from alcohol/ether; m.p. 143 C.

EXAMPLE 14 EXAMPLE 15 5 g. of 5-hydroxy-4-hydroxymethyl-3- methylthiomethyl-6-methyl-pyridine is heated in 30 ml of 75 percent acetic acid to 80 C; thereafter, a solution of 2 g. of CrO in 6 ml of water is added dropwise. The temperature of the reaction mixture is maintained at 7080 C for l hour. Then, the mixture is concentrated under vacuum, mixed with water, and continuously extracted with ethyl acetate. The ethyl acetate extract is dried over Na,SO concentrated by evaporation, and the residue treated with alcoholic l-lCl. The thus-precipitated 5-hydroxy-4-hydroxymethyl-3- methylsulfinylmethyl-fi-methyl-pyridine hydrochloride is vacuum filtered and recrystallized from alcohol/ether; m.p. 179 C.

EXAMPLE l6 Analogously to Example 12, 3-allylsulfinylmethyl-5- hydroxy-4-hydroxymethyl-6-methyl-pyridine hydrochloride is produced by reacting 3-allythiomethyl-5- hydroxy-4-hydroxymethyl-6-methyl-pyridine hydrochloride with 30 percent H O m.p. 140 C (decomposition) (alcohol/ether).

EXAMPLE l7 Analogou'sly to Example 12, 5-hydroxy-4- hydroxymethyl-6-methyl-3-propargylsulfinylmethylpyridine hydrochloride is prepared by reacting 5- hydroxy-4-hydroxymethyl-6-methyl-3-propargylthiomethyl-pyridine hydrochloride with 30 percent H m.p. 158 C (decomposition) (methanol/ether).

EXAMPLE 18 9 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-5- mercapto-methyl-pyridine is dissolved in an excess of acetic anhydride; several ml of anhydrous pyridine are added; and the reaction mixture is allowed to stand overnight in a cooled water bath. The thus-cooled reaction product is mixed with water, acidified to a pH of 2-3, and heated for 30 minutes to 60-80 C. After cooling, the aqueous phase is extracted with ether in an extractor. The dried ether solution is freed of the solvent by allowing an appropriate amount of boiling absolute alcohol to flow into the solution. HCl is introduced into the cooled, alcoholic solution, and after standing overnight, 2-methyl-3-hydroxy-4- hydroxymethyl--acetylthiomethyl-pyridine hydrochloride is crystallized from the reaction mixture. Yield: 85 percent of theory. M.p.: 160 C. after recrystallization from alcohol-ether.

EXAMPLE 19 In a round flask, 9.24 g. of isopropylidene-5- thiopyridoxine is dissolved in 200 ml of ether and mixed with an ether-diazomethane solution until the yellow color persists. After 1 hour, the excess of diazomethane is removed by the dropwise addition of dilute acetic acid, and the solvent is thereupon evaporated.

The residue is mixed with 100 ml of 0.01N hydrochloric or sulfuric acid or another mineral acid and heated on a steam bath for 30 minutes. After cooling, the reaction mixture is extracted several times with ethyl acetate, dried, the solvent removed by evaporation, and the remaining substance mixed with HCl-saturated, dry alcohol. When allowing the reaction mixture to stand overnight, 2-methyl-3-hydroxy-4-hydroxymethyl-5- methylthiomethyl-pyridine hydrochloride crystallizes. Yield: 87 percent of theory; m.p. 155 C.

EXAMPLE 20 A solution of 1.7 g. of lauric acid chloride in 5 ml of chloroform is added dropwise to a solution of 2.0 g of isopropylidene-S-thiopyridoxine HCl in 20 ml of chloroform and 10 ml. of pyridine. After allowing the reaction mixture to stand overnight, it is first washed with water in a separatory funnel and then with 0.5N HCl. The separated chloroform phase is dried and concentrated by evaporation. The oily residue (2 g.) is boiled under reflux with 20 ml of water, 40 ml of alcohol and 8 ml of N HCl for 10 minutes, and then freed of the solvent under vacuum. The residue crystallizes upon treatment with isopropyl ether. After recrystallization from ethyl acetate/alcohol, the 2-methyl-3-hydroxy-4- hydroxymethyl-S-laurylthiomethyl-pyridine melts at 118l 19 C. By stirring together with alcoholic HCI, the hydrochloride is obtained, m.p. C.

EXAMPLE 21 11 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-5-thiomethylpyridine hydrochloride is added to a solution of 6.2 g. of potassium hydroxide in ml of methanol, and then mixed with 8.5 g. of B-methylthioethyl bromide. The reaction mixture is heated for 2 hours in a steam bath and substantially freed of the solvent. The residue is extracted with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and then removed by evaporation. After mixing with alcoholic hydrochloric acid, and allowing the reaction mixture to stand overnight, 2-methyl-3-hydroxy-4- hydroxymethyl-S-(fi-methylthioethylthiomethyl)- pyridine crystallizes as the hydrochloride.

EXAMPLE 22 In the course of 1 hour, a cooled solution of 6.1 g. of ethylene sulfide in alcohol is added dropwise to a well stirred and ice-cooled solution of 18.5 g. of 2-methyl-3- hydroxy-4-hydroxymethyl-5-thiomethyl-pyridine in a mixture of 2.5 g. of sodium and 200 ml. of absolute alcohol; thereafter, the reaction mixture is stirred at room temperature for another hour. The residue is acidified with acetic acid, and dry hydrogen chloride is introduced, whereupon, after allowing the reaction mixture to stand in a refrigerator overnight 2-methyl- 3hydroxy-4-hydroxymethyl-5-(thioethylthiomethyl)- pyridine crystallizes.

EXAMPLE 23 Under stirring and icecooling, 60 g. of 2-methyl-3- hydroxy-4-hydroxymethyl-5-thiomethyl-pyridine are introduced batchwise into ml of ethylenimine in such a manner that the temperature does not exceed +10 C. After terminating the addition, the reaction mixture is stirred under cooling for another 2 hours. The thus-precipitated reaction product is vacuum filtered, washed with either (m.p. of the base: l56158 C) and coverted, by suspending the reaction product in alcoholic hydrochloric acid, into the hydrochloride of 2-methyl-3-hydroxy-4-hydroxymethyl-S-(B- =aminoethyl)-thiomethyl-pyridine, which melts at 212C .after recrystallization from methanol/ether.

EXAMPLE 24 22 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-S-thi-; omethylpyn'dine hydrochloride is suspended in 200 mlof ethanol; under stirring, 12.4 g. of potassium hydroxide is added thereto. The stirring is continued for an-1 other hour, and then the reaction mixture is filtered and the filtrate thereafier mixed with 17 g. of isopropyl iodide. After allowing the reaction mixture to stand overnight, it is vacuum filtered from the thusprecipitated potassium iodide. The filtrate is evaporated under vacuum, and the residue disolved in alcoholic hydrochloric acid. The thus-obtained crude 2- methyl-3-hydroxy-4-hydroxymethyl-5-(isopropylthiomethyl)-pyridine hydrochloride melts, after recrystallization from methanol/ether, at l35l 36 C. Yield: 21

EXAMPLE 25 To a solution of 29 g. of KOH in 300 ml of methanol, 39.6 g. of thioacetic acid is added. Under ice-cooling, 68 g. of isopropylidene-S '-chloropyn'doxine HCl is then introduced into the solution, and the reaction mixture is allowed to stand overnight. The thusprecipitated potassium chloride is vacuum filtered on a glass frit, and the filtrate evaporated under vacuum. From the filtrate residue, mixed with alcoholic HCl and ether, there crystallizes 70 g. or 96 percent of theory of 3,4'-isopropylidene-5-acetylthiomethylpyridoxine as the hydrochloride, m.p. 180 C.

In order to split ofi the isopropylidene group, the residue of the vacuum evaporation step is mixed with 300 ml of 0.01N sulfuric acid and heated on a steam bath for 30 minutes. The cooled solution is extracted with ether; the ether solution is dried and then evaporated. The residue of the evaporation is mixed with alcoholic HCl and allowed to stand overnight in a regrigerator.

Yield: 76 percent of theory of 2-methyl-3-hydroxy-4- hydroxyniethyl-S-acetylthiomethyl-pyridine hydrochloride, m.p. 160 C.

EXAMPLE 26 8 g. of 2-methyl-3-hydroxy-4-hydroxymethyl-5- methylsulfinylmethyl-pyridine-N-oxide is dissolved in glacial acetic acid; then, with gentle heating on a water bath, 24 g. of zinc dust is introduced into the reaction solution. After the evolution of hydrogen has termi- EXAMPLE 27 18.1 g. of 2-methyl-3-hydroxy-4-( 1- adamantyloxycarbonyl)-amino-S-thiomethyl-pyridine is dissolved in 50 percent dioxane. Thereafter, an equivalent amount (5.11 g.) of pivalic acid (2,2,2- trimethylacetic acid) is added, where upon 10.35 g. of dicyclohexyl carbodiimide, dissolved in ml of percent dioxane, is added dropwise under stirring.

After 4 hours, the reaction mixture is filtered from the thus-separated dicyclohexylurea, and the solvent is removed by evaporation under vacuum at a temperature which is as low as possible. The crude 2-me'thyl-3- hydroxy-4-( l-adamantyl-oxycaibonyl)-amino-5- pivalylthiomethyl-pyridine remaining as the residue is taken up in 2N hydrochloric acid, and then 1 l g. of soldium nitrite is introduced. After the evolution of nitrogen has ended, the reaction mixture is stirred for another hour at room temperture and then extracted with ethyl acetate. The dried solution is freed of the solvent, and the residue is taken up in ethanolic hydrochloric acid. Upon allowing the reaction mixture to stand overnight in a refrigerator, 2-methyl-3-hydroxy-4- hydroxymethyl-5-pivalylthiomethyl-pyridine hydrochloride crystallizes.

EXAMPLE 28 To a solution of 18.5 g. of 2-methyl-3-hydroxy-4- hydroxymethyl-S-thiomethyl-pyridine in 4 g. of sodium-methylate-containing absolute ethanol, there is added dropwise under stirring within 2 hours 10.1 g. of methyl acrylate in such gradual a manner that, optically by external cooling, the temperature in the reaction vessel can be maintained at 50 C 1 5 C. After the addition step is terminated, the reaction mixture is additionally heated under stirring for 2 hours at 50 C in order to complete the reaction. Then, the reaction mixture is cooled, filtered if necessary, and concentrated by evaporation to about one-third of the original volume; then, the solution is saturated with dry hydrogen chloride. The thus-precipitated mixture of sodium chloride and ester hydrochloride is washed with as small an amount of water as possible, to remove the sodium chloride; then, the reaction mixture is recrystallized from alcoholic hydrochloric acid. Thus, the pure 2-methyl-3-hydroxy-4-hydroxymethyl-(5- carbomethoxyethylthiomethyl)-pyridine tained.

HCl is ob- EXAMPLE 29 8.7 g. of vinyl actate is mixed, batchwise and under ice-cooling, with 18.5 g. of 2-methyl-3-hydroxy-4- ihydroxymethyl-S-thiomethyl-pyridine. After the reaction mixture is allowed to stand overnight, the reaction mixture is triturated with ether to form a precipitate. The latter is vacuum filtered, washed with ether, and recrystallized from ethanol. methanol. thus-obtained 2-methyl-3 hydroxy-4-hydroxyrnethyl-5-( B- =acetoxyethylthiomethyl)-pyridine melts at 224 C.

EXAMPLE 30 2 g. of Z-methyl-3-hydroxy-4-hydroxymethyl-5- methylthiomethyl-pyridine is dissolved in 30 ml of acetonitrile. The solution is allowed to stand for 3 days with 1.5 g. of methyl iodide and is then filtered off from any precipitate. The filtate is concentrated. The crys- :tals which separate after allowing the concentrated filtrate to stand overnight in a refrigerator are vacuum filtered and washed with a small quantity of cold methanol. After recrystallization from methanol, the thusobtained 2-methyl-3-hydroxy-hydroxymethyl-5- methylthiomethyl-pyridinium iodide melts at 165C. Yield: 0.8 g. 7

EXAMPLE 31 a. 10 g S-mercaptomethyl-Z,2-8-trimethyl-4H-mdioxino [4,5-c] pyridinehydrochloride were dissolved in ml pyridine and 100 ml of acetic anhydride were added. After 12 hours the precipitated pyridine hydrochloride was filtered off, the volatile components were distilled off and after trituration with ether the residue was crystallized. There was obtained S-acetylmercaptomethyl-2,2-8-trimethyl-4l-l-m-dioxino {4,5-c] pyridine; base M.P. C; hydrochloride: M.P. l89-l 90 C (from alcoholic hydrochloric acid with ether). Quantitative yield.

I dihydrochloride. M.P. ;hydrochloric acid).

b. Heating with 0.01 N H 80 (respectively l-lCl) during 10 minutes to 100 C, yields after neutralization,

85 percent of crude 5-hydroxy-4-hydroxyrnethyl-3- acetylthiomethyl-6-methylpyridine; M.P. 144 C (from methanol).

EXAMPLE 32 a. To a solution of 7 g KOH in 200 ml methanol there are added successively 16 g 5-mercaptomethyl-2,2-8- trimethyl-4H-m-dioxino [4,5-c] pyridinhydrochloride :and 8.7 g methyl iodide and the reaction mixture was left to stand for 12 hours at 20 C. After addition of 1 liter water, extraction in the cold with ethyl acetate and drying over sodium sulfate the liquid was evaporated and the residue was converted by treatment with alcoholic hydrochloric acid to 13.6 g (85 percent) of 5- methylthiomethyl-2,2-8-trimethyl-4H-m-dioxino [4,5-

c] pyridinhydrochloride; M.P. 186 C.

By heating the compound obtained under a) with 1 N HCl (half an hour, 100 C) and evaporation of the volatile components there was obtained in a quantitative manner 5-hydroxy-4-hydroxymethyl-3-methylthiomethyl-6-methylpyridinehydrochloride; M.P. l54-155 C (dec. (from ethanol/ether) EXAMPLE 33 a. 4 g 5-[(2-chloroethyl)-thiomethyl]2,2-8-trimethyl- 4H-m-dioxino [4,5-c] pyridinehydrochloride where inserted together with 50ml benzene and 50 ml condensed anhydrous dimethyl-amine into a carius tube which was closed by smelting, and heated in a tube oven during 10 hours to a temperature between 60 and 70 C. After cooling and opening of the carius tube the dimethylamino hydrochloride was filtered off and the liquid was evaporated. There was obtained 5-[(2- dimethylaminoethyl)thiomethyl]-2,2-8-trimethyl-41-1- 'm-dioxino-[4,5-c] pyridine.

b. The residue obtained according to a) was heated together with 100 ml N l-lCl during 25 minutes to 100 C and the solution was concentrated by evaporation.

There was obtained 5-hydroxy-4-hydroxymethyl-3[(2- dimethylamino)ethyl]-thiomethyl-6-methylpyridine 195-196 C (from ethanol EXAMPLE 34 A quantity of 70 ml of 1 N HCl was poured over 5.76 g of (5-acetoxy-4-acetoxymethyl-3-methylthiomethylf6-methyl)pyridine and heated during 30 minutes on a steam bath. All volatile components were distilled off from the still hot solution. A residue consisting of 5- hydroxy-4-hydroxymethyl-3-methylthiomethyl-6- methyl-pyridinehydrochloride was obtained, quantitative yield, M.P. 155 C (dec).

EXAMPLE 35 A quantity of 3.14 g of 5-[(2-Nitroethyl) thiomethyl- ]-2,2-8-trimethyl-4l-l-m-dioxino [4,5-c]-pyridine -N- oxide were dissolved in 150 ml of absolute methanol and hydrated at room temperature under atmospheric pressure on 0.3 g platinum dioxide till take up of hydrogen ceased. After filtering off the catalyst and evaporatiion, the residue was recrystallized from alcoholic hydrochloric acid. There was obtained a 95 percent yield of 5-hydroxy-4-hydroxymethyl-3-[(2- aminoethyl)thiomethyl1-6-methylpyridinedihydrochloride of M.P. 212 C.

38 EXAMPLE 36 A quantity of 18.5 g 5-hydroxy-4-hydroxymethyl-3- mercaptomethyl-6-methyl-pyridine was added to a so lution of 6.2 g potassium hydroxide and 7.85 ml of 3- chloropropionitril and left at 20 C during 12 hours. After removal of the solvent the residue was extracted with ethyl acetate. There was obtained 5-hydroxy-4- hydroxymethyl-3-[(Z-cyanethyl)thiomethyl1-6- methylpyridine M.P. 150C (from ethyl/acetate). Yield: 21.9 g (92 percent).

EXAMPLE 37 To a solution of 9.2 g of 5-hydroxy-4hydroxymethyl- 3-mercaptomethyl-6-methylpyridine and 3.1 g KOH in 50 ml methanol there was added 7.65 g to ethoxyethylbromide. The reaction mixture was stirred during 12 hours. The solid components were sucked off and extracted with ethyl acetate. The filtrate and the ethyl acetate extracts were united and concentrated by removal of solvent. There was obtained 5-hydroxy-4- hyroxymethyl-3-[ (2-ethoxy )ethylthiomethyl ]-6- methylpyridine. M.P. 99 C (from ethyl acetate). Yield: 78.2 percent.

EXAMPLE 38 EXAMPLE 39 9.25 g of 5-hydroxy-4-hydroxymethyl-3- mercaptomethyl-6-methyl-pyridine were dissolved in a mixture of 3.1 g KOH in ml methanol and 6.83 g of 6-chloro-n-hexanol-(1) were added. After heating for 2 hours at 100 filtration and removal of solvents the residue wasextracted with ethyl acetate. After evaporation there was obtained 11.1 g (78 percent) of 5- hydroxy-4-hydroxymethyl-3-[(6-hydroxy-n-hexyl)- thiomethyl -6-methylpyridine M.P. C (decomposition, from isopropanol).

EXAMPLE 40 4.7 g of 5-hydroxy-4-hydroxymethyl-3- mercaptomethyl-methyl-pyridine were mixed with 8.6 g of maleic acid diethylester and after addition of 50 ml of sodium methylate heated during 1 hour to 100 C. Upon cooling, there precipitated a crystalline precipitate, which was dissolved in acetic acid and filtered. From the filtrate there precipitated upon addition of hexane 5-hydroxy-4-hydroxymethyl-3-[(l,2- diethoxycarbonyl)-ethyl-thiomethyl -6-methylpyridine, M.P. 103 C (from ethyl acetate/hexane) Yield: 7.7 g (87 percent).

EXAMPLE 41 In an analogous manner to Example 40 there was obtained from 4.7 g of 5-hydroxy-4-hydroxymethyl-3- 

2. A member as defined by claim 1 wherein R1 is -S-; and R2 is -COCH3, -COC (CH3)3, allyl, propargyl, lower alkyl or linear unsubstituted alkyl of up to 20 C-atoms, lower alkyl substituted in the W position by one member selected from the group consisting of -Cl, -Br, -OH, -SH, -SCH3, NH2, NHCH3, NHC2H5, -N(CH3)2, -N(C2H5)2, N(C3H7)2, N(C4H9)2, N(C6H13)2, -COOH, -COOCH3, -COOC2H5, -OCOCH3, -CN, -OC2H5 and -COCH3.
 3. A member as defined by claim 1, wherein R1 represents S and R2 represents CH3.
 4. A member as defined by claim 1, wherein R1 represents
 5. A member as defined by claim 1, wherein R1 represents S and R2 represents n-C4H9.
 6. A member as defined by claim 1, wherein R1 represents S and R2 represents n-C5H11.
 7. A member as defined by claim 1, wherein R1 represents S and R2 represents -CH3, n-C3H7, i-C3H7,-C4H9, -C5H11, -C6H13, -C7H15, -C8H17, -C9H19, -C10H21, -C16H33, -C18H37, -C20H41, -(CH2)2N(CH3)2, -CH2CH(NH2)COOH, -CH2OH, -CH2COOC2H5, -CH2CH CH2, -CH2-C*CH, -COCH3, -(CH2)2SCH3, -(CH2)2SH, -(CH2)2NH2, -COC(CH3)3, -(CH2)2COOCH3, -(CH2)2OCOCH3, -(CH2)2CN, -(CH2)2OC2H5, -CH2CH(OH)CH3, -(CH2)5-CH2OH, -CH(COOC2H5)CH2COOC2H5, -CH(CH3)-CH2COOC2H5, -CH2CH(OH)CH2OH, -(CH2)2-CH2Br, -(CH2)2CH2OH, -(CH2)2CH2SH,-(CH2)2COOH, -CH2CH2CH CH-COCH3, -CH2CH(Br)CH3, -CH2CH(Br)CH2Br, -CH2CH(Br)CH2OH, -CH2CH2CH(C1)CH3, -CH2-CH(OH)CH3, -CH2 CH2CH(OH)CH3, -CH2CH2N(C4H9)2, -CH2CH2CH2NH2, -CH2COOH, CH2CH(NH2)COOC2H5, -CH(CH3)COOH, -CH2CH(OC2H5)2, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, -CH2CH2NHC2H5, -CH2CH2N(C2H5)2, -CH2CH2N(C3H7)2or-CH2CH2N(C6H13)2.
 8. A member as defined by claim 1, wherein R1 represents
 9. A member as defined by claim 1, wherein R2 is unsubstituted alkyl.
 10. A member as defined by claim 9, wherein R2 is n-C5H11, n-C4H9 or CH3.
 11. A member as defined by claim 9, wherein R1is -S-.
 12. A member as defined by claim 10, wherein R1is -S-. 